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Journal of Virology, October 2005, p. 12714-12720, Vol. 79, No. 20
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.20.12714-12720.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Cathepsin L Is Involved in Proteolytic Processing of the Hendra Virus Fusion Protein

Cara Theresia Pager and Rebecca Ellis Dutch*

Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky 40536-0509

Received 24 May 2005/ Accepted 18 July 2005

Proteolytic processing of paramyxovirus fusion (F) proteins is essential for the generation of a mature and fusogenic form of the F protein. Although many paramyxovirus F proteins are proteolytically processed by the cellular protease furin at a multibasic cleavage motif, cleavage of the newly emerged Hendra virus F protein occurs by a previously unidentified cellular protease following a single lysine at residue 109. We demonstrate here that the cellular protease cathepsin L is involved in converting the Hendra virus precursor F protein (F0) to the active F1 + F2 disulfide-linked heterodimer. To initially identify the class of protease involved in Hendra virus F protein cleavage, Vero cells transfected with pCAGGS-Hendra F or pCAGGS-SV5 F (known to be proteolytically processed by furin) were metabolically labeled and chased in the absence or presence of serine, cysteine, aspartyl, and metalloprotease inhibitors. Nonspecific and specific protease inhibitors known to decrease cathepsin activity inhibited proteolytic processing of Hendra virus F but had no effect on simian virus 5 F processing. We next designed shRNA oligonucleotides to cathepsin L which dramatically reduced cathepsin L protein expression and enzyme activity. Cathepsin L shRNA-expressing Vero cells transfected with pCAGGS-Hendra F demonstrated a nondetectable amount of cleavage of the Hendra virus F protein and significantly decreased membrane fusion activity. Additionally, we found that purified human cathepsin L processed immunopurified Hendra virus F0 into F1 and F2 fragments. These studies introduce a novel mechanism for primary proteolytic processing of viral glycoproteins and also suggest a previously unreported biological role for cathepsin L.

* Corresponding author. Mailing address: Department of Molecular and Cellular Biochemistry, University of Kentucky, College of Medicine, Biomedical Biological Sciences Research Building, 741 South Limestone, Lexington, KY 40536-0509. Phone: (859) 323-1795. Fax: (859) 323-1037. E-mail: rdutc2{at}uky.edu.

Journal of Virology, October 2005, p. 12714-12720, Vol. 79, No. 20
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.20.12714-12720.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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